Today’s post was prompted by a reader who saw a very positive response from the L-type calcium channel blocker, Amlodipine.
So we return to the subject of calcium
channels.
The good news about calcium channel
defects is that many are easy to treat.
In most single gene autisms (Rett,
Fragile-X, Pitt Hopkins etc) the underlying problem is that a faulty gene does
not do its job of producing the expected protein. This is a problem of too little.
In many ion channel dysfunctions the
problem is not too little, it is too much expression. For example, in Timothy
Syndrome the mutation in the gene produces too much of the protein, in this
case the L-type calcium channel Cav1.2.
Ion channel dysfunctions can be the
result of a faulty gene, or just that the on/off switch for that gene is
faulty. Fortunately, the problem is
usually that it is stuck “on”.
In people who develop Type-1 diabetes we have seen how the disease process can be halted by blocking Cav1.2 in the
pancreas. This halts the decline in the
beta cells that produce insulin.
Once all the beta cells are dead, the
person cannot produce insulin and has type-1 diabetes. Treating the person
after this point with a Cav1.2 blocker will provide no benefit; the damage has
already been done
Something similar happens in
Parkinson’s disease, but this time you need to block Cav1.3. In the early stages of the disease Cav1.3 is
over-expressed in a key part of the brain, which triggers a slow process of
degeneration. Treating a person with all the visible symptoms of Parkinson’s
with a Cav1.3 blocker will provide no benefit; the damage has already been
done.
Calcium channel
blockers are not very specific
The current drugs used to block
calcium channels were mainly developed to treat heart conditions.
When treating neurological disorders
like autism we are primarily focused on the brain, what goes on
elsewhere can also be very relevant, but in an indirect way.
In the brain the important calcium channels are: -
L type
N type
P type
R type
T type
Plus, Inositol trisphosphate receptor (IP3R) and Ryanodine receptors. IP3R
has been covered in previous posts.
Verapamil (a Phenylalkylamine class drug)
Verapamil blocks L type channels and T type channels, plus some potassium ion channels.
When it comes to specific L type
channels there are 4, Cav1.1, Cav1.2, Cav1.3, and Cav1.4.
In the brain we have just Cav1.2 and
Cav1.3. Verapamil mainly affects Cav1.2.
Amlodipine (a Dihydropyridine
class drug)
Amlodipine blocks L type channels and
N type channels.
Amlodipine mainly affects Cav1.3.
Nicardipine (a Dihydropyridine
class drug)
Nicardipine blocks L type channels and
N type channels.
As a Dihydropyridine, it should mainly
affect Cav1.3.
In addition, it blocks the sodium ion
channel Nav1.8.
The effect on Nav1.8 is why it has
been proposed as a therapy for Pitt Hopkins. In this syndrome Nav1.8 is over
expressed as a downstream consequence of a mutation in the TCF4 gene.
Effect on P
channels
To some extent Verapamil, Amlodipine
and Nicardipine all block P channels.
P channels are called P after the
Purkinje neurons, where they are located. These Purkinje cells likely define
some aspects of autism, because of their absence. Purkinje neurons are among
the largest in the brain, with elaborate dendritic arbor. I imagine this makes them vulnerable.
In the people with severe autism most
of the Purkinje cells appear to have died.
Blocking P channels might have
protected Purkinje cells from death.
The effect of too much L-type calcium channel signaling on behavior
You can both turn on self-injury via
activating L type calcium channels and extinguish it by blocking the same
channels. It is proven in mice and seems
to apply to at least some humans.
Calcium
channel activation and self-biting in mice
The L type calcium channel agonist (±)Bay K 8644 has been reported to cause characteristic motor abnormalities in adult mice. The current study shows that administration of this drug can also cause the unusual phenomenon of self-injurious biting, particularly when given to young mice.
The self-biting provoked by (±)Bay K 8644 can
be inhibited by pretreating the mice with dihydropyridine L type calcium
channel antagonists such as nifedipine, nimodipine, or nitrendipine. However,
self-biting is not inhibited by nondihydropyridine antagonists including
diltiazem, flunarizine, or verapamil.
(±)Bay K 8644 functions as an L type calcium
channel activator that increases calcium fluxes in response to depolarizing
stimuli (19–21). In rodents, this drug has been reported to produce characteristic motor
abnormalities including impaired ambulation, twisting and stretching movements,
transient limb extension, back arching, spasticity, ataxia, or catatonia
(22–28). Some studies have anecdotally noted the
occurrence of SIB with this drug (23–25, 27), though this phenomenon has received little
attention. The current
study shows that (±)Bay K 8644 will reliably provoke SB and SIB under
certain conditions in mice, providing a tool to study the neurobiology of this
unusual behavior.
When I first encountered the above study,
I did wonder why Verapamil did not extinguish the self-injury.
It turns out that Bay K 8644 is a modified
version of the common drug nifedipine, which is a Cav1.3 blocker. Verapamil is mainly a Cav1.2 blocker. Bay K 8644 is like the opposite of nifedipine.
In the trial they have activated Cav1.3 causing excess calcium inside neurons. The only way to block this process is to block Cav1.3. Blocking Cav1.2 with Verapamil could not solve the problem.
Note that activation of Cav1.3 can cause motor abnormities in mice and this might be seen as ataxia in a human. One particular reader of this blog will see the relevance of this.
I did write extensively in earlier
posts about the large amount of research that links L type calcium channels to neuropsychiatric
disorders.
I did mainly focus on Cav1.2 using Verapamil, but the evidence for the role of Cav1.3 is clear as day.
L-type calcium channels as drug targets in CNS disorders
L-type calcium channels are present in most electrically excitable cells and are needed for proper brain, muscle, endocrine and sensory function. There is accumulating evidence for their involvement in brain diseases such as Parkinson disease, febrile seizures and neuropsychiatric disorders. Pharmacological inhibition of brain L-type channel isoforms, Cav1.2 and Cav1.3, may therefore be of therapeutic value.
From Gene to
Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric
Symptoms.
The L-type calcium channels (LTCCs) Cav1.2 and Cav1.3, encoded by the CACNA1C and CACNA1D genes, respectively, are important regulators of calcium influx into cells and are critical for normal brain development and plasticity. In humans, CACNA1C has emerged as one of the most widely reproduced and prominent candidate risk genes for a range of neuropsychiatric disorders, including bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder.
Here, we provide a review of clinical studies that have evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, as well as rodent studies that have identified Cav1.2- and Cav1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.
Was I surprised that Amlodipine, that
targets Cav1.3 rather than Cav1.2, was very beneficial in someone with severe
autism? Not at all.
I was interested that the effect was
more pro-cognitive than anti-anxiety. Is
that the effect on Cav1.3 or is it via that N channel Cav2.2?
N-type calcium channels are important
in neurotransmitter release because they are localized at the synaptic
terminals. Piracetam, the original cognitive enhancing drug, is also a N type
channel blocker.
Statins and L
type calcium channels blockers – it matters which one you choose
We previously saw how the statin class of drugs can be beneficial in autism, but it depends which one you chose. For example, in SLOS (Smith-Lemli-Opitz syndrome), where both copies of the gene DHCR7 are mutated, you need to push the gene to work. To increase expression of this gene you need Simvastatin. This is hard for people to understand because SLOS features very low cholesterol and statins are thought of as cholesterol lowering drugs. The body needs the enzyme DHCR7 to make cholesterol and Simvastatin increases DHCR7 expression.
In the case of L type channel blockers, the selection is very important. The effect
will not be the same.
If you have a mutation in Cav1.2, you
would expect Verapamil to be a good choice.
If the mutation is in Cav1.3, you would expect Amlodipine to be better.
If you have over expression of T
channels (Cav3.1, Cav3.2 or Cav3.3) then you would expect a benefit from
Verapamil and none from Amlodipine.
If you have over expression of the N
channel (Cav2.2) then you would want Amlodipine
If you have over expression of the
sodium channel Nav1.8 then you would want Nicardipine
Conclusion
It is likely that many people with autism,
bipolar, ADHD or schizophrenia might benefit from treating their ion channel dysfunctions. The required drugs are cheap generics that
have been in your local pharmacy for a few decades.
Back in 2019 I wrote the post below:
Cheap
common drugs may help mental illness
I highlighted a new study, using historic
data from Sweden, that looked at the secondary effects of statins, calcium
channel blockers and metformin on psychiatric hospitalization.
Question
Are drugs in common use for physical health problems (hydroxylmethyl glutaryl
coenzyme A reductase inhibitors, L-type calcium channel antagonists, and
biguanides) associated with reduced rates of psychiatric hospitalization and
self-harm in individuals with serious mental illness?
Findings In this series of within-individual cohort studies of 142 691 patients with bipolar disorder, schizophrenia, or nonaffective psychosis, exposure to any of the study drugs was associated with reduced rates of psychiatric hospitalization compared with unexposed periods. Self-harm was reduced in patients with bipolar disorder and schizophrenia during exposure to all study drugs and in patients with nonaffective psychosis taking L-type calcium channel antagonists.
We found that periods of HMG-CoA RI (statin) exposure were
associated with reduced psychiatric hospitalization in all subgroups of SMI (Serious
Mental Illness) and with reduced self-harm in BPD and schizophrenia.
Exposure to LTCC (L type calcium channel) antagonists was
associated with reduced rates of psychiatric hospitalization and self-harm.
Periods of metformin (a type 2 diabetes drug) exposure were
associated with reduced psychiatric and nonpsychiatric hospitalization across
all SMI subgroups.
Use of L
type calcium channel blockers reduces self-harm.
How much
more evidence is needed?
I took an
educated guess several years ago that Verapamil would tame summertime raging in
my son. It was the only calcium channel
blocker I tried and it worked. This year we had the emergence of extreme sound
sensitivity. My educated guess was that blocking potassium channels with
Ponstan (Mefenamic acid) would resolve the problem, and it did.
Treating ion
channel dysfunctions (channelopathies) in autism clearly is not rocket science;
it is just waiting to be attempted.